Glutamic acid is one of the 20 amino acids commonly found in animal proteins. Only the L-stereoisomer occurs in mammalian proteins. Like aspartic acid, glutamic acid has an acidic carboxyl group on its side chain which can serve as both an acceptor and a donor of ammonia, a compound toxic to the body. Once glutamic acid has coupled with ammonia, it is called glutamine and can as such safely transport ammonia to the liver, where the ammonia is eventually converted to urea for excretion by the kidneys. Free glutamic acid (that not incorporated into proteins) can also be converted reversibly to xcex1-ketoglutaric acid, an intermediate in the Krebs cycle, and as such can be degraded to carbon dioxide and water, or transformed into sugars. The acidic side chain of glutamic acid confers one negative charge under most conditions to proteins in which this amino acid is found, thus increasing the water solubility of the protein. Monosodium glutamate (MSG), the monosodium salt of L-glutamic acid, is widely used as a condiment. The amino acid was isolated from wheat gluten in 1866 and chemically synthesized in 1890. It is not essential to the human diet, since it can be synthesized in the body from the common intermediate xcex1-ketoglutaric acid.
The fluid produced by the prostate gland contains significant amounts of glutamic acid, and this amino acid may play a role in normal function of the prostate. In one study, symptoms of benign prostatic hyperplasia (BPH) were improved in a group of forty-five men taking 780 mg of glutamic acid per day for two weeks and then 390 mg for the next two and a half months in combination with equal amounts of the amino acids alanine and glycine, an effect also reported by other researchers. See Damrau, F. xe2x80x9cBenign prostatic hypertrophy: Amino acid therapy for symptomatic reliefxe2x80x9d, J. Am Geriatr Soc 1962; 10(5):426-30; and Feinblatt, H. M. and Gant, J. C. xe2x80x9cPalliative treatment of benign prostatic hypertrophy. Value of glycine-alanine-glutamic acid combinationxe2x80x9d, J. Maine Med Assoc March 1958.
L-Glutamate is one of the most abundant excitatory amino acid neurotransmitters found in the mammalian brain. This amino acid acts on diverse glutamate receptors including members of both the ionotropic and metabotropic glutamate receptor (mGluR) families. Brxc3xa4uner-Osborne, H.; Egebjerg, J.; Nielsen, E.; Madsen, U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609; and Nakanishi, S. Science 1992, 258, 597; Blasi, A. D.; Conn, P. J.; Pin, J. P.; Nicoletti, F. Trends Pharmacol. Sci. 2001, 22, 114. Because of the possibility to identify ligands that may prove useful in disease intervention, considerable attention has been given to the discovery of both selective agonists and antagonists of these glutamate receptors over the past decade. Mukhopadhyaya, J. K.; Kozikowski, A. P.; Grajkowska, W.; Pshenichkin, S.; Wroblewski, J. T. Bioorg. Med. Chem. Lett., in press; Kozikowski, A. P.; Steensma, D.; Araldi, G. L.; Pshenichkin, S.; Surina, S.; Wroblewski, J. T. J. Med. Chem. 1998, 41, 1641.
One aspect of the present invention relates to 2-hydroxymethylglutamic acid and congeners thereof. A second aspect of the invention relates to a method of synthesizing 2-hydroxymethylglutamic acid and congeners thereof.